The major histocompatibility complex (MHC) includes histocompatibility antigens, polymorphic membrane glycoproteins found on the surface of nearly all cells. One individual simultaneously expresses polymorphic forms from a large pool of alleles in the population. Rejection of foreign tissue transplants is initiated by antibody and cytotoxic lymphocyte (CTL) recognition of Class I histocompatibility antigens. T-cell receptors only recognize foreign antigens that are associated with a particular histocompatibility antigen molecule.
As known to one of skill in the art, MHC molecules bind an intracellular foreign peptide antigen, transport the bound antigen to the surface of the cell membrane, and present the antigen for recognition by T-cells. T-cell recognition of antigen-bound MHC molecules then initiates a cascade of events in the immune response.
In organ transplantation, despite major advances in surgical techniques and the development of new drugs, the majority of transplant recipients remain at high risk for rejection. Currently available therapies to prevent rejection rely on broad spectrum immunosuppressive drugs such as cyclosporin A (CsA), which must be taken through out the individual's life. The cumulative effects of such long-term immunosuppression include opportunistic infections, cancers, and drug-specific toxicity. It would be of great utility to develop a therapeutic system administered only in the perioperative period which could thereby avoid the long-term effects of immunosuppression.
Prior attempts to alleviate organ transplant rejection using the MHC molecule have included administration of whole donor cells, which express donor-type MHC antigens. This method requires pre-operative administration of the alloantigen, and thus has only limited clinical applicability because of the need for donor-identification well in advance of the time of transplantation. It would be highly desirable to develop an effective therapeutic system which could be administered at the time of transplantation.